A Master Class in Hormone Levels and Doses in Menopause

Understanding the Concerns with Ultra-High Doses

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Panorama is a BBC investigative documentary series with the tagline that they reveal “the truth about the stories that matter.” Recently, one of those stories was menopause, or more specifically, the menopause industry. An article on the episode can be found here. 

The episode focused on two aspects of the menopause industry: supplements (shocker, none discussed were worthwhile medically speaking) and the medical care that a group of women reportedly received at a private menopause clinic in the United Kingdom run by Dr. Louise Newson, a general practitioner. Dr. Newson is a regular fixture on British television and in the UK print media, and she has a massive presence on social media. She has shaped a lot of important conversations about menopause, so concerns about the care some women reportedly received at her clinic must have been considered important for the general public. 

A lot of the reporting in the Panorama episode centered around the fact that the doses of estrogen recommended from the Newson clinic were higher than licensed in the UK and that the women may have experienced complications as a result. In addition, the women were not aware the doses they were receiving were not considered standard of care. 

We heard during the episode from both the patients and some of the former providers at the Newson Clinic that when symptoms persisted, the answer seemed to be to increase the dose of estrogen. We also saw a video of a “secret shopper,” a reporter who made an online appointment with the Newson Clinic, and despite reporting that she was already on a 100 mcg estradiol patch (the highest licensed dose in the UK), she was told she could double or triple the dose and that Dr. Newson herself was using 300 mcg transdermal. The investigation could not tell us what percentage of women who have attended the Newson clinic are on these ultra-high doses, but we did learn that the British Menopause Society “removed Dr. Newson from its register of menopause specialists” due to “concerns that “aspects of her practice” did not fit with “established guidance”.” 

Ultra-high doses of estrogen are also prescribed in the United States and Canada, typically in the form of hormone pellets and sometimes even injections, but may also occur with compounded therapies as well. While practitioners who prescribe ultra-high doses of estradiol might claim they have data that supports this practice, the truth is that without prospective, randomized, double-blinded, quality peer-reviewed clinical trials, those kinds of claims are unsupported. Retrospective data won’t cut it here, especially as many women with complications may not follow up with their original prescribing clinic, and hormone therapy has a high placebo response rate. 

Since this story broke, I have received many questions about hormone doses and levels, so I think reviewing the science and the research is valuable. I am typically asked a lot about doses and levels anyway, so this was a good time to also pull some questions out of the vault and really tackle the topic. I have grouped all the questions I received into several broader categories. The questions and answers pertain to general practices, not specific individuals.  

Five pieces of housekeeping. 

1. I will use both the US (pg/ml) and UK (pmol/L). I will use the US units first because I am most familiar with them (to convert from pg/ml to pmol/L, you multiply by 3.67, but I’ll do the math for you). 

2. I will use estradiol patch as a general term, which also applies to the equivalent doses of other estrogen formulations. Here is a table from the British Menopause Society for those in the UK to convert between a patch and other estrogens. Remember that the way the UK converts from transdermal estradiol to oral differs from the US and Canada, where we consider a 100 mcg patch equivalent to 2 mg of oral estradiol. 

3. I will use the term unstudied, ultra-high dose estradiol to refer to any estrogen prescription over 100 mcg patch or equivalent (so also pellets and injections) for someone who is still menstruating or for anyone in menopause. Primary ovarian insufficiency, early surgical menopause, and premature menopause (between ages 40 and 45) may have more wiggle room, but those are different medical situations. 

4. The estradiol levels of concern discussed here do not apply to fertility therapy. Those are brief ups and downs, meaning within a cycle. With ultra-high doses of estradiol, we’re talking about exposures for weeks, months, or possibly even years.

5. Nothing here is individual medical advice.

Lastly, this is a relatively technical post, so I will give you the summary up front! If you just want to take my word for it, then you only have to read the summary. But if you want to do a deep dive to see my supporting evidence, I’ve got you covered as well, and you should keep reading to the end. 

Summary of What We Know About Doses of Hormone Therapy for Menopause

• There is no data to support starting every woman age 45 or up in menopause or women in the menopause transition on a 100 mcg patch. Women with primary ovarian insufficiency should start with a 100 mcg patch. 

• For women in the menopause transition, a 100 mcg patch has been studied for depression, and this is an acceptable starting dose for that indication.

• No menopause society recommends routine blood tests to guide dosing. If studies showed that blood tests were worthwhile, they would be included in the guidelines.

• Estradiol levels can underestimate estrogen exposure due to how hormones are metabolized, making estrogen seem low when it is not.

• There is no quality, peer-reviewed, prospective evidence that women in the menopause transition or menopause at the typical time need ultra-high doses of estradiol or higher blood levels. 

• There is no good data to support the claim that up to 20% of women are poor absorbers of estrogen. 

• Ultra-high doses of estrogen can cause tachyphylaxis, which can make people feel awful and be mistaken for inadequate estrogen therapy when really there is too much estrogen.

• There is no data to say a 300 mcg patch is safe. All recent safety data is with doses of 150 mcg or less. Higher doses could be harmful in ways we can’t predict, and the risk of endometrial cancer is very concerning. 

• Ultra-high doses, like a 300 mcg patch, should not be compared with the birth control pill. 

• MHT can make symptoms worse in the menopause transition as it doesn’t help the fluctuations in hormones and makes high levels of estradiol even higher. The pill is often the best option here as it stops ovulation and stops the chaos. 

Was the summary not enough? Okay, fasten your seatbelts….

Claim: Women Need Blood Tests to Ensure They Have a “Physiologic Level” of Estradiol.

Response: Unsupported by the Evidence.

The claim that women must achieve “physiologic levels” of estradiol is always somewhat vague. What is a physiologic dose and which study supports this? As you might suspect, there are no quality studies that suggest we should be aiming for a specific estradiol level. This is why we recommend treating based on symptoms.

A physiologic level means what the body would normally be producing, and in menopause, that is estradiol levels < 20 pg/ml (73.4 pmol/ml). However, there is new data with more accurate testing that suggests normal levels in menopause may be < 10 pg/ml. A physiologic level in menopause would be giving no estrogen since that is what the body would normally produce. So yeah. Maybe not. 

Estradiol levels range from 20-800 pg/ml (73-2937 pmol/L) during a typical menstrual cycle, and the levels change daily, higher around ovulation. One reference places the average estradiol level over the entire menstrual cycle between 100 and 126 pg/ml (367-462 pmol/L) and another between 81-163 pg/ml (300‒600 pmol/L). Levels in the early follicular phase are 20-80 pg/ml (73-294 pmol/L), and I’ve seen an average of about 61 pg/ml (224 pmol/ml) quoted in the early follicular phase. While it seems logical that we should give women with primary ovarian insufficiency the average dose of estradiol that they should be experiencing pre-menopause, and there are at least three randomized trials that support this approach, it seems absurd that we would design menopause hormone therapy to replicate levels seen in the menstrual cycle. After all, women don’t have menopause symptoms in their early follicular phase. The goal of menopause hormone therapy isn’t to prepare a body for pregnancy; it’s to treat symptoms and protect the bones. 

Studies tell us that lower levels than the average across a normal menstrual cycle can easily treat symptoms for many and protect bone health. An older study (1985) that looked at estradiol levels and an estradiol patch reported that symptoms were well treated when estradiol levels were between 61 pg/mL (224 pmol/l) and 122 pg/mL (448 pmol/L). However, this is an older study, and the methods for measuring estradiol may not be as accurate as they are today. In KEEPS (2016), women used a 50 mcg patch or placebo (we’ll exclude the Premarin arm for simplicity), and for those women who received the patch, hot flashes were significantly improved with an estradiol level of 44 pg/mL (161 pmol/l). Another study of a patch that isn’t available showed both a 20 mcg and a 40 mcg patch improved hot flashes by about 84%, and the resulting estradiol levels were 25 to 31 pg/mL (92-114 pmol/L) for the 20 mcg patch and 40 to 51 pg/ml (147-187) for the 40 mcg estradiol patch. And, of course, these doses make sense because that is a normal estradiol level at the start of the menstrual cycle. Even a patch with 14 mcg of estradiol has been shown to reduce hot flashes by 75% for 41% of women.

For many years, it was believed that the minimal estradiol level for bone health was 30-45 pg/ml (110-165 pmol/l), and some papers did propose an estradiol level of 60 pg/ml (220 pmol/L). Further work suggests that bone is exquisitely sensitive to estradiol, and the recommendation now is not to check levels and to simply prescribe the equivalent of a 25 mcg-100 mcg patch as we know that dose protects bone for women of the average age of menopause and above (age 45 and up). However, a case could be made for starting with a higher than 25 mcg for a higher-risk individual. A 12.5 mcg patch does offer some bone protection, although possibly not as much, but it is an option for those sensitive to estrogen. 

As an aside, apparently, some functional health nutritionists are claiming that transdermal estradiol doesn’t protect the bone, and they are trying to get you to do a DUTCH test (read more about why a DUTCH test isn’t helpful here) to prove to you that you need oral therapy, or some such nonsense. Don’t take advice about hormones from someone who can’t prescribe them! 

Let’s look at the transdermal estradiol patches, Vivelle, for the 37.5 mcg patch and up. If we say the early follicular phase has levels of 30-50 pg/ml of estradiol, then every patch will generally be in that range, except for a few outliers using 37.5 or a 50 mcg patch. If these women have symptoms, we just bump up one or two levels.   

There is no evidence to suggest that every woman should start with a 100 mcg estradiol patch, given many women have their symptoms adequately treated with doses as low as 25 mcg. Many factors must be considered regarding a starting hormone dose, including age, symptoms, previous experiences with hormones, the risk for endometrial cancer, the risk for breast cancer, breast density, whether someone is in the menopause transition or menopause if they have migraines and risk for blood clots. And, of course, personal patient preference. Some want to start low and increase if needed, and others want to start at the maximum given symptom severity and then consider gradually reducing over time. The dose of estrogen someone may need at age 50 to control symptoms may be higher than they need at 55, so clinical reassessment is also key. 

A 100 mcg patch is the dose studied in the menopause transition for depression, and so there may be specific situations where that dose is recommended. 

No menopause society recommends checking levels because the studies tell us that we can go by symptoms and a little logic. If you are age 50 and your period stopped two years ago, and a 50 mcg patch isn’t helping enough for hot flashes or night sweats, you can increase it. How much? To 75 mcg or 100 mcg, depending on current side effects, symptoms, and underlying risk for endometrial cancer. If you get to a 100 mcg patch and symptoms persist, then your symptoms may not be treatable with estrogen, or you may be in the minority who does not absorb well (we’ll get to those issues shortly). Might some younger women need slightly higher doses? Possibly, but most people wouldn’t go from 100 mcg to 200 mcg; they would increase to 125 mcg or possibly just try a different delivery system, such as a gel or oral therapy.

Also, it’s ALWAYS important to consider when a high dose of estradiol, 100 mcg patch, isn’t working, what ELSE might be causing the symptoms?

Why do so many people seem to be pushing hormone levels? They do make money for some healthcare professionals. The blood tests themselves are typically not particularly expensive (although the DUTCH urine test apparently is), but many doctors charge to interpret them, so it’s a way for some to increase payment. Tests also provide an illusion of caring, and this may be especially important with the expensive concierge services we see in the United States, where women may pay $1,500 or even $3,000 for a visit. Look, when you charge a small fortune in the United States, you have to do things, like tests, to make the high price seem worthwhile.

Another big issue with relying on tests to aim for “physiologic” levels is that an estradiol level doesn’t give us the whole picture of how much estrogen the tissues see. Estradiol has a complex intracrinology, meaning the blood level of estradiol may not reflect what is happening at the tissue level. For example, with transdermal administration, estradiol is also converted into estrone, so measuring only estradiol levels can even underestimate the amount of estrogen that is available to the tissues. Other variables can also affect levels. 

It’s important to state that since we have no studies on managing hormone doses based on hormone levels, we also have no idea how these tests perform in real-time. 

Finally, during the menopause transition, meaning when women are still having periods, testing blood levels is worse than useless. They can be up and down because of the normally irregular changes, so we have no idea what is from the MHT and what is from the ovaries. 

It’s about the studied doses and the symptoms, not the levels. Women will have individual responses to therapy, hence the dosing range between 25 and 100 mcg patches. 

Claim: Some Women Just Need Higher Blood Levels 

Response: Not Supported by Quality, Peer Reviewed Published Data

Some women have told me that they were advised that they might need estradiol levels of 163 pg/ml (600 pmol/L) or higher to feel well, but this is not supported in the literature. First of all, if the average estradiol level for the menstrual cycle ranges from 81-163 pg/ml (300‒600 pmol/L), the levels in the early follicular phase are 20-80 pg/ml (73-294 pmol/L), and the average estradiol level in the early follicular phase is about 61 pg/ml (224 pmol/ml), why would it take MORE estrogen as a woman ages to feel better? 

I’ve just laid out in painful detail how studies tell us that women generally find their symptoms well treated with doses of 100 mcg or often much less. Given that the placebo response with hormone therapy can be very high and the unknown health risks with doses over 100 mcg, my opinion is that higher doses must be tested with rigorous prospective placebo-controlled studies before they can be offered.

One very real concern with ultra-high doses of estradiol and why women may feel unwell if they reduce their dose or feel unwell so they keep increasing their dose is they may be experiencing tachyphylaxis, which is a decreased response to a drug with increasing doses. This can lead to a cycle of higher and higher doses, and, in the case of estrogen, the side effects can be depression, anxiety, irritability, and headaches. These side effects could be mistaken for not receiving enough estrogen when, in fact, the opposite is true. More is not necessarily better. Remember, estradiol levels may inform us of what is happening at the tissue level. Tachyphylaxis has previously been seen mostly with injections, but it has been described with transdermal Oestrogel, which resulted in an estradiol level of 287 pg/ml (1052 pmol/L). Human beings are not designed to have pre-ovulatory estradiol levels for weeks at a time. 

There is real potential harm in a knee-jerk response of just escalating estrogen when someone isn’t feeling well. First of all, there is the risk of tachyphylaxis. In addition, physicians are ruling out approaches that might have been more effective by not considering other therapies. For example, if the issue is insomnia despite a 100 mcg patch, then the next step may be evaluation in a sleep clinic and likely CBT-I (cognitive behavioral therapy for insomnia). Or if someone has depression, instead of doubling an estradiol patch from 100 mcg to 200 mcg, the next option is almost certainly consulting a mental health professional and possibly an antidepressant. And so on. And, of course, we don’t know the risks of ultra-high doses of estrogen. 

Claim: High Doses, Like a 300 mcg Patch, Have the Same Estrogen Dose as The Pill, so They Must be Safe.  

Response: No, and Bad Comparison 

First of all, we don’t reliably know what women absorb with a 300 mcg patch, so comparing this dose with the pill isn’t possible. However, the package insert for the estradiol-containing pill, Zoely, reports an average estradiol level of 50 pg/ml, so a 300 mg patch will be more than that pill. 

What about an ethinyl estradiol-containing pill? A direct conversion is hard for various biochemical reasons, but let’s say, for argument, it is an equivalent dose as a 300 mcg patch; that would mean it’s not safe to use over age 50-55 (50 in the UK and 55 in the US) We believe that staying on a birth control pill with ethinyl estradiol beyond age 50-55 increases the risk of cardiac complications and stroke. That is not exactly a rousing recommendation to be on a 300 mcg patch long-term. 

Also (and this is big), with the estrogen-containing birth control pill, the dose of progestin to protect the uterus has been determined, but we have no idea what to give women who are using a 300 mcg patch to protect their uterus; we can only guess.

I often wonder why so many cash-only doctors here in the United States seem so hesitant to prescribe the estrogen-containing pill for the menopause transition when it can be awesome. My theory is it’s because the pill is often $5 or maybe even free and available for a very low-cost or even no-cost visit in many places, so it’s pretty hard to justify charging $1500 for a visit and then turn around and send them home with a $5 pill. 

Claim: Up to 20% of Women are Poor Absorbers of Estradiol. 

Response: No Good Supporting Evidence

Several people asked about “5-20%” being poor absorbers. The best that I can tell is that this claim may come from the introduction of a review article from 2002 that looked at the published data for estrogen levels and bone health with hormone therapy. Heading further down the rabbit hole, it seems the references from this paper for the “5-20%” poor absorber claim are from book chapters, one from 1994 and the other from 1998, and I can’t access them. The science behind measuring estrogen levels has changed, so we need more recent data than references in books from the 1990s, especially when we have data from KEEPS and, of course, from all the pharmaceutical companies that had to show estradiol absorption to the FDA. Interesting side note: the article that sent me down the “5-20%” rabbit hole concludes that estrogen levels with hormone therapy might not be very useful in predicting osteoporosis risk. 

We know there is a range of absorption of estradiol, as there is with most medications, and most studies tell us that most women will absorb enough with the standard doses, hence why they are the standard doses. 

Regardless, “poor absorber” is never defined. What level makes someone a poor absorber? If you have estradiol levels of 40 pg/ml or higher, estradiol is getting in your blood. Is a poor absorber 50 pg/ml (184 pmol/L)? 95 pg/ml (350 pmol/L)? Is it 163 pg/ml (600 pmol/L)? And after what dose? How often do you check? How long after administering a dose of gel or applying a patch? These things all matter and would need robust clinical trials to sort out. 

It’s true that a minority of women may not absorb transdermal estradiol well, and this seems to be mostly a patch issue. In one study treating primary ovarian insufficiency, 18 women taking 100-150 mcg estradiol patches had their estradiol level checked after being on therapy for a year, and the average was 110 pg/ml (range 76-145) or 406 pmol/L (range 280 – 532). No outlier with a super low estradiol level was mentioned, so no poor absorber was mentioned. I’ve pulled several studies that look at levels with transdermal therapy, and none mention outliers that didn’t absorb, although truthfully, these studies usually have less than 200 women, so a rate of 1% or less might be missed.

But to be a poor absorber, we need a definition. Do we say that someone with an estradiol level of 70 pg/ml (257 pmol/L) on a 100 mcg patch is a poor absorber, or are they just at the low end of the bell curve (because someone has to be at the low end of the bell curve, that is how distribution curves work)? It's impossible to say without studies of so-called poor absorbers matching levels with symptoms.  

If someone were in menopause, meaning no period for the past 12 months and on a 100 mcg patch and is still having terrible hot flashes or sleeping poorly (nocturnal hot flashes might be under recalled) or symptoms I would expect to resolve with estrogen, I would consider doing a one-time estradiol level to make sure it’s at least around 50 pg/ml. If it’s lower, she may be a poor absorber, but because absorption can be erratic and the test results have a margin of error, I would not give her more of what she isn’t absorbing; I’d likely suggest switching to a different transdermal system or to oral therapy. If her estrogen level were in an expected range, I’d look for other causes of her symptoms and other therapies. I still might even suggest a different estrogen delivery system to see if that worked better because, as I already noted, levels may not tell us what is happening at the cell level. 

I can’t emphasize enough that when someone isn’t responding as expected to a 100 mcg patch, they should also look for other causes. For example, if someone reports they have developed hot flashes again despite being on estrogen and they just started Zoloft, that’s likely the cause. They may need to be tested for diabetes, thyroid disease, and iron deficiency, to name a few. 

And then there is the menopause transition. Once again, testing hormone levels is useless. But what’s even more important to know is many of the symptoms that women experience in the menopause transition are related to erratic levels of hormones or even higher levels of estrogen, not lower levels of estrogen, and a 100 mcg patch or even higher won’t help erratic or high levels of estrogen because it doesn’t suppress ovulation. In fact, in this situation, extra estrogen can often make symptoms worse, as the high levels of estradiol are made even higher by the patch. 

In many scenarios in the menopause transition, the best approach is the birth control pill, as that prevents the wild swings in hormone levels and replaces them with a steady level. 

Claim: Ultra-high Doses of Estradiol are Safe

Response: No Data Supports That Claim

Really, we have no data. We can only guess what dose of progesterone or progestin is needed to protect the uterus from endometrial cancer with 200 or 300-mcg patches, hormone pellets, or injections. We don’t know the risk of blood clots, stroke, or high blood pressure, and we don’t know if these doses can trigger endometriosis or adenomyosis or if they pose a different risk for breast cancer.

We just don’t know. 

****

In my opinion, ultra-high doses of estradiol should be evaluated with quality clinical trials to understand claims and risks. Without that data, there can really be no informed consent.

The various menopause society guidelines about doses and not doing hormone levels are based on the best science currently available, and using ultra-high doses of estrogen, whether it’s a truckload of patches and gels or pellets or injections, and then monitoring with estradiol levels is uncharted territory. It is a matter of public safety that women know we don't fully understand the risks of these regimens and that we are really in the dark about how best to protect them from endometrial cancer. Hormone pellet use isn’t that common where I am, although I’ve seen my fair share of complications, but some of my colleagues see an alarming number. I've yet to see or hear of a patient who knew exactly how understudied her therapy was.

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